Novel, non-invasive markers for detecting therapy induced neuroendocrine differentiation in castration-resistant prostate cancer patients

AbstractNeuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.

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The Correlation between PSCA Expression and Neuroendocrine Differentiation in Prostate Cancer

BioMed Research International ◽

10.1155/2020/5395312 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Qian Xiang ◽

Zhiguo Zhu ◽

Lianmin Luo ◽

Jiamin Wang ◽

Yangzhou Liu ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Specific Antigen ◽

Neuroendocrine Differentiation ◽

Positive Association ◽

Tumor Stage ◽

Clinicopathological Parameters ◽

Specific Marker ◽

Castration Resistant Prostate Cancer ◽

Neuroendocrine Prostate Cancer

The prostate stem cell antigen (PSCA), as a predominantly prostate-specific marker, is overexpressed in most prostate cancer specimens, is positively correlated with prostate cancer androgen independence, and has the potential to be treated with castration-resistant prostate cancer (CRPC) as a gene therapy target. Using the typical androgen deprivation therapy, most tumors will progress to CRPC, as well as develop into neuroendocrine prostate cancer (NEPC) characterized by the expression of neuroendocrine markers such as enolase 2 (NSE). Our study was aimed at investigating the expressions of PSCA and NSE and the relationship between the two markers, as well as the correlation between the PSCA and NSE expressions and the clinicopathological parameters in prostate cancer specimens from 118 patients by using immunohistochemistry. Our results demonstrated that the PSCA and NSE protein expressions did not correlate with the prostate cancer patients’ age or the hormone therapy but showed a significant correlation with the pathological tumor stage of prostate cancer, the Gleason score, and the presence of metastasis. There is a positive association between PSCA and NSE but a negative one between the prostate-specific antigen (PSA) and PSCA or between PSA and NSE. High PSCA and NSE expressions correlated with a poor prognosis in prostate cancer patients. PSCA may play an important role in the progression of neuroendocrine prostate cancer (NEPC).

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Why castration-resistant prostate cancer patients with neuroendocrine differentiation should be addressed to a cisplatin-based regimen

Annals of Oncology ◽

10.1093/annonc/mdp456 ◽

2009 ◽

Vol 20 (12) ◽

pp. 2019-2020 ◽

Cited By ~ 1

Author(s):

F. Vignani ◽

L. Russo ◽

M. Tucci ◽

M. Motta ◽

G. Vellani ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Neuroendocrine Differentiation ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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Sympathetic signaling facilitates progression of neuroendocrine prostate cancer

Cell Death Discovery ◽

10.1038/s41420-021-00752-1 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Shubham Dwivedi ◽

Maricris Bautista ◽

Sanskriti Shrestha ◽

Hussain Elhasasna ◽

Tanaya Chaphekar ◽

...

Keyword(s):

Prostate Cancer ◽

Neuroendocrine Differentiation ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Neuroendocrine Prostate Cancer ◽

Intervention Point ◽

High Concentrations ◽

Potential Therapeutic Intervention

AbstractThe progression of prostate cancer (PC) into neuroendocrine prostate cancer (NEPC) is a major challenge in treating PC. In NEPC, the PC cells undergo neuroendocrine differentiation (NED); however, the exact molecular mechanism that triggers NED is unknown. Peripheral nerves are recently shown to promote PC. However, their contribution to NEPC was not studied well. In this study, we explored whether sympathetic neurosignaling contributes to NED. We found that human prostate tumors from patients that later developed metastases and castration-resistant prostate cancer (CRPC), a stage preceding to NEPC, have high sympathetic innervations. Our work revealed that high concentrations of the sympathetic neurotransmitter norepinephrine (NE) induces NED-like changes in PC cells in vitro, evident by their characteristic cellular and molecular changes. The NE-mediated NED was effectively inhibited by the Adrβ2 blocker propranolol. Strikingly, propranolol along with castration also significantly inhibited the development and progression of NEPC in vivo in an orthotopic NEPC model. Altogether, our results indicate that the NE-Adrβ2 axis is a potential therapeutic intervention point for NEPC.

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Loss of EHF facilitates the development of treatment-induced neuroendocrine prostate cancer

Cell Death and Disease ◽

10.1038/s41419-020-03326-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhi Long ◽

Liang Deng ◽

Chao Li ◽

Qiangrong He ◽

Yao He ◽

...

Keyword(s):

Prostate Cancer ◽

Transcriptional Repression ◽

Critical Role ◽

Histone H3 ◽

Neuroendocrine Differentiation ◽

Cell Models ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Neuroendocrine Prostate Cancer ◽

Aggressive Subtype

AbstractThe rising of a highly aggressive subtype of castration-resistant prostate cancer (CRPC) named treatment-induced neuroendocrine prostate cancer (t-NEPC) after androgen deprivation therapy (ADT) is well known for its features of the neuroendocrine differentiation (NED) and androgen receptor (AR) independence. However, t-NEPC is still largely unknown. Here, we found that EHF is notably depressed in t-NEPC tumors, patient-derived xenografts, transgenic mice, and cell models. Results from cell lines uncovered that ADT represses EHF expression, which is required for the ADT-induced NED. Mechanism dissection revealed that ADT decreases the EHF transcription via relieving the AR binding to different androgen-responsive elements, which then promotes the expression and enzymatic activity of enhancer of zeste homolog 2 (EZH2), consequently catalyzing tri-methylation lysine 27 of histone H3 for transcriptional repression of its downstream genes to promote the NED. Furthermore, preclinical studies from cell and mice models proved that recovery of EHF expression or using EZH2 inhibitor can attenuate aggressive properties of CRPC cells, hinder the progression of t-NEPC, and promote the response of CPRC cells to enzalutamide. Together, we elucidate that the ADT/AR/EHF/EZH2 signaling is required for the ADT-enhanced NED and plays a critical role in the progression of t-NEPC.

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The Crosstalk of Long Non-Coding RNA and MicroRNA in Castration-Resistant and Neuroendocrine Prostate Cancer: Their Interaction and Clinical Importance

International Journal of Molecular Sciences ◽

10.3390/ijms23010392 ◽

2021 ◽

Vol 23 (1) ◽

pp. 392

Author(s):

Che-Yuan Hu ◽

Kuan-Yu Wu ◽

Tsung-Yen Lin ◽

Chien-Chin Chen

Keyword(s):

Prostate Cancer ◽

Median Survival ◽

De Novo ◽

Neuroendocrine Differentiation ◽

Cancer Development ◽

Current Evidence ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Neuroendocrine Prostate Cancer ◽

Epigenetic Regulators

Prostate cancer is featured by its heterogeneous nature, which indicates a different prognosis. Castration-resistant prostate cancer (CRPC) is a hallmark of the treatment-refractory stage, and the median survival of patients is only within two years. Neuroendocrine prostate cancer (NEPC) is an aggressive variant that arises from de novo presentation of small cell carcinoma or treatment-related transformation with a median survival of 1–2 years from the time of diagnosis. The epigenetic regulators, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been proven involved in multiple pathologic mechanisms of CRPC and NEPC. LncRNAs can act as competing endogenous RNAs to sponge miRNAs that would inhibit the expression of their targets. After that, miRNAs interact with the 3’ untranslated region (UTR) of target mRNAs to repress the step of translation. These interactions may modulate gene expression and influence cancer development and progression. Otherwise, epigenetic regulators and genetic mutation also promote neuroendocrine differentiation and cancer stem-like cell formation. This step may induce neuroendocrine prostate cancer development. This review aims to provide an integrated, synthesized overview under current evidence to elucidate the crosstalk of lncRNAs with miRNAs and their influence on castration resistance or neuroendocrine differentiation of prostate cancer. Notably, we also discuss the mechanisms of lncRNA–miRNA interaction in androgen receptor-independent prostate cancer, such as growth factors, oncogenic signaling pathways, cell cycle dysregulation, and cytokines or other transmembrane proteins. Conclusively, we underscore the potential of these communications as potential therapeutic targets in the future.

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